title: Pro-inflammatory action of MIF in acute myocardial infarction via activation of peripheral blood mononuclear cells.
abstract: OBJECTIVE
  Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, has been implicated in the pathogenesis of multiple inflammatory disorders. We determined changes in circulating MIF levels, explored the cellular source of MIF, and studied the role of MIF in mediating inflammatory responses following acute myocardial infarction (MI).
  
  
  RESULTS
  We recruited 15 patients with MI, 10 patients with stable angina and 10 healthy volunteers and measured temporal changes of MIF in plasma. Expression of MIF, matrix metalloproteinase-9 (MMP-9) and interleukin-6 (IL-6) in cultured peripheral blood mononuclear cells (PBMCs) and the media were measured by ELISA or real-time PCR. Compared to controls, plasma levels of MIF and IL-6 were significantly elevated at admission and 72 h post-MI. In contrast, expression of MIF, MMP-9 and IL-6 by PBMCs from MI patients was unchanged at admission, but significantly increased at 72 h. Addition of MIF activated cultured PBMCs by upregulating expression of inflammatory molecules and also synergistically enhanced stimulatory action of IL-1β which were inhibited by anti-MIF interventions. In a mouse MI model we observed similar changes in circulating MIF as seen in patients, with reciprocal significant increases in plasma MIF and reduction of MIF content in the infarct myocardium at 3 h after MI. MIF content in the infarct myocardium was restored at 72 h post-MI and was associated with robust macrophage infiltration. Further, anti-MIF intervention significantly reduced inflammatory cell infiltration and expression of monocyte chemoattractant protein-1 at 24 h and incidence of cardiac rupture in mice post-MI.
  
  
  CONCLUSIONS
  MI leads to a rapid release of MIF from the myocardium into circulation. Subsequently MIF facilitates PBMC production of pro-inflammatory mediators and myocardial inflammatory infiltration. Attenuation of these events, and post-MI cardiac rupture, by anti-MIF interventions suggests that MIF could be a potential therapeutic target following MI.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia ; Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: White
authors.forename: Lu
authors.initials: L
authors.lastname: Fang
authors.forename: William
authors.initials: W
authors.lastname: Chan
authors.forename: Eric F
authors.initials: EF
authors.lastname: Morand
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Duffy
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Taylor
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Dart
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D004195:Disease Models, Animal; D006342:Heart Rupture, Post-Infarction / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D009203:Myocardial Infarction / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012307:Risk Factors; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D053583:Interleukin-1beta; D015850:Interleukin-6; D008263:Macrophage Migration-Inhibitory Factors